1. Field of the Invention
The present invention includes methods for treating conditions modulated by lactosylceramide and, more particularly, to the use of one or more compounds that inhibit UDP-galactose, GlcCer, .beta.1-&gt;4 galactosyltransferase (GalT-2) to treat a subject suffering from or susceptible to a condition caused or contributed to by lactosylceramide. The present invention also relates to methods for detecting and analyzing compounds with therapeutic capacity to treat such conditions.
2. Background
Uncontrolled cell proliferation relates to conditions impacting the heart, kidney, liver and other organs. For example, uncontrolled cell proliferation is indicative of diseases such as certain vasculopathies, e.g., atherosclerosis, and pathologies involving neovascularization, tumor or cyst development, e.g., polycystic kidney disease and post-surgical keloid formation. In particular, uncontrolled proliferation of vascular cells can significantly contribute to disease by occluding blood flow and enhancing vessel remodeling. Certain post-surgical disorders such as restenosis are particularly affected by uncontrolled vascular cell proliferation. See generally Harrison's Principles of Internal Medicine, (1991) 12 ed. McGraw-Hill, Inc.; and Cole, B. R. (1990) in The Cystic Kidney, Dordrecht, Netherlands.
Invasive surgical procedures have been developed to alleviate certain diseases and post-surgical disorders. For example, certain surgical techniques involving angioplasty, and particularly balloon angioplasty, have been developed to enhance vascular flow. However, angioplasty is often accompanied by side effects such as restenosis. In particular, restenosis is recognized as a serious post-surgical complication of angioplasty. See Landau, C., et al. (1994) N. Eng. J Med, 330:981 and references cited therein.
Further attempts to alleviate diseases and post-surgical disorders impacted by uncontrolled cell proliferation have employed certain therapeutic agents. For example, there has been much effort to develop agents that can reduce restenosis after angioplasty. More specifically, probucol is a recognized therapeutic agent that has been reported to reduce restenosis in some patients. However, existing probucol-based therapies are believed to be ineffective due to unsatisfactory patient tolerance and insufficient reduction of stenoses. See e.g., Tardif, J. C. et al., (1997) N. Eng. J. Med, 337:365-372; Ferns, G. A. A. et al. (1992) PNAS (U.S.A.) 89:11312 and references cited therein.
Efforts have been made to develop therapies that treat or prevent conditions affected by cell proliferation. For example, one approach has been to identify agents with therapeutic capacity to modulate cell pathways involving glycosphingolipids (GSLs). The GSLs are believed to impact lipid storage diseases, particularly glycosphingolipidoses and perhaps other lipid-related pathologies. See e.g., Chatterjee, S., Biochem. Biophys. Res Comm. (1991) 181:554; Hakomori, S. I. (1983) in Sphingolipid Chemistry, eds. Kanfer, J. N. and Hakomori, S. I. (Plenum Press, New York) and references cited therein.
Certain biochemical steps relating to GlcCer and LacCer have been disclosed. For example, one step involves synthesis of GlcCer by coupling UDP-glucose to ceramide in a reaction catalyzed by UDP-glucose glucosyltransferase (GlcT-1). Another step converts the GlcCer to LacCer using UDP-galactose, GlcCer, .beta.1-&gt;4 galactosyltransferase (GalT-2). See e.g., Chatterjee et al. supra
Attempts have been made to inhibit biochemical steps involving GlcT-1. For example, it has been reported that D-1-phenyl-2-decanolylamino-3-morpholino-1-propanol (D-PDMP) inhibits GlcT-1 and reduces proliferation of vascular cells. The mechanism of PDMP has been reported to be unclear. See e.g., Felding-Habermann, B., et al. (1991) Biochemistry 29:6314; Shukla, G. S. et al. Biochem. Biophys. Acta. (1991) 1083:101; Inokuchi, J. et al., J. Lipid. Res. (1987) 28:565; Chattejee, S., supra.
Specified morpholinoceramides also have been disclosed as GlcT-1 inhibitors. See Carson, K. and B. Ganem (1994) Tetrahedron Lets. 35:2659.
Other cell functions are believed to play a role in conditions modulated by LacCer. For example, uncontrolled cell adhesion is believed to effect specified immune responses such as allergic reactions and host rejection of foreign tissue.
It has been reported that uncontrolled cell proliferation and cell adhesion can affect certain vasculopathies. For example, atherosclerosis is believed to be worsened by adhesion of certain immune and vascular cells. Plaque formation is particularly enhanced by cell proteins such as intercellular adhesion molecule-1 (ICAM-1, CD54) and vascular cell adhesion molecule-1 (VCAM-1). See e.g., Kume, N. et al. (1992) J. Clin. Invest. 90:1138; Iademarco, M. F. et al. (1995) J. Clin. Invest. 95:264; Carlos, T. et al. Blood (1991) 77:2266; Nagel, T. et al. (1994) J. Clin. Invest. 94:885; and Cybulsky, M. I. and Gimbrone M. A. (1991) Science 251:788.
Certain GSLs also have been reported to be cell receptors for bacterial toxins. For example, cellular uptake of cholera toxin is believed to be enhanced by a membrane-associated GSLs.
Thus, it would be desirable to have additional methods of treating conditions or diseases modulated by lactosylceramides, e.g. to inhibit GalT-2, in order to treat or prevent such conditions.